2uzu: Difference between revisions

Revision as of 19:51, 21 February 2008

PKA STRUCTURES OF INDAZOLE-PYRIDINE SERIES OF AKT INHIBITORS

OverviewOverview

Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

About this StructureAbout this Structure

2UZU is a Protein complex structure of sequences from Bos taurus with as ligand. Active as cAMP-dependent protein kinase, with EC number 2.7.11.11 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension., Zhu GD, Gandhi VB, Gong J, Thomas S, Woods KW, Song X, Li T, Diebold RB, Luo Y, Liu X, Guan R, Klinghofer V, Johnson EF, Bouska J, Olson A, Marsh KC, Stoll VS, Mamo M, Polakowski J, Campbell TJ, Martin RL, Gintant GA, Penning TD, Li Q, Rosenberg SH, Giranda VL, J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25. PMID:17523610

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 ==Overview==
-Compound 7 was identified as a potent (IC50 = 14 nM), selective, and, orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt., While promising efficacy was observed in vivo, this compound showed, effects on depolarization of Purkinje fibers in an in vitro assay and CV, hypotension in vivo. Guided by an X-ray structure of 7 bound to protein, kinase A, which has 80% homology with Akt in the kinase domain, our, efforts have focused on structure-activity relationship (SAR) studies of, the phenyl moiety, in an attempt to address the cardiovascular liability, and further improve the Akt potency. A novel and efficient synthetic route, toward diversely substituted phenyl derivatives of 7 was developed, utilizing a copper-mediated aziridine ring-opening reaction as the key, step. To improve the selectivity of these Akt inhibitors over other, protein kinases, a nitrogen atom was incorporated into selected phenyl, analogues of 7 at the C-6 position of the methyl indazole scaffold. These, modifications resulted in the discovery of inhibitor 37c with greater, potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular, safety profile. The SARs, pharmacokinetic profile, and CV safety of, selected Akt inhibitors will be discussed.
+Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
 ==About this Structure==
@@ Line 15: / Line 15: @@
 [[Category: cAMP-dependent protein kinase]]
 [[Category: Bouska, J.]]
-[[Category: Campbell, T.J.]]
+[[Category: Campbell, T J.]]
-[[Category: Diebold, R.B.]]
+[[Category: Diebold, R B.]]
-[[Category: Gandhi, V.B.]]
+[[Category: Gandhi, V B.]]
-[[Category: Giranda, V.L.]]
+[[Category: Giranda, V L.]]
 [[Category: Gong, J.]]
 [[Category: Guan, R.]]
-[[Category: Johnson, E.F.]]
+[[Category: Johnson, E F.]]
 [[Category: Klinghofer, V.]]
 [[Category: Li, Q.]]
@@ Line 28: / Line 28: @@
 [[Category: Luo, Y.]]
 [[Category: Mamo, M.]]
-[[Category: Marsh, K.C.]]
+[[Category: Marsh, K C.]]
 [[Category: Olson, A.]]
-[[Category: Penning, T.D.]]
+[[Category: Penning, T D.]]
 [[Category: Polakowski, J.]]
-[[Category: Rosenberg, S.H.]]
+[[Category: Rosenberg, S H.]]
 [[Category: Song, X.]]
-[[Category: Stoll, V.S.]]
+[[Category: Stoll, V S.]]
 [[Category: Thomas, S.]]
-[[Category: Woods, K.W.]]
+[[Category: Woods, K W.]]
-[[Category: Zhu, G.D.]]
+[[Category: Zhu, G D.]]
 [[Category: L20]]
 [[Category: akt inhibitors]]
@@ Line 53: / Line 53: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:48:50 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:51:57 2008''